This invention relates to novel conformationally restricted aromatic compounds which inhibit microsomal triglyceride transfer protein, and to methods for decreasing serum lipids and treating atherosclerosis employing such compounds.
The microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride (TG), cholesteryl ester (CE), and phosphatidylcholine (PC) between small unilamellar vesicles (SUV). Wetterau and Zilversmit, Chem. Phys. Lipids 38, 205-22 (1985). When transfer rates are expressed as the percent of the donor lipid transferred per time, MTP expresses a distinct preference for neutral lipid transport (TG and CE), relative to phospholipid transport. The protein from bovine liver has been isolated and characterized. Wetterau and Zilversmit, Chem. Phys. Lipids 38, 205-22 (1985). Polyacrylamide gel electrophoresis (PAGE) analysis of the purified protein suggests that the transfer protein is a complex of two subunits of apparent molecular weights 58,000 and 88,000, since a single band was present when purified MTP was electrophoresed under nondenaturing condition, while two bands of apparent molecular weights 58,000 and 88,000 were identified when electrophoresis was performed in the presence of sodium dodecyl sulfate (SDS). These two polypeptides are hereinafter referred to as 58 kDa and 88 kDa, respectively, or the 58 kDa and the 88 kDa component of MTP, respectively, or the low molecular weight subunit and the high molecular weight subunit of MTP, respectively.
Characterization of the 58,000 molecular weight component of bovine MTP indicates that it is the previously characterized multifunctional protein, protein disulfide isomerase (PDI). Wetterau et al., J. Biol. Chem. 265, 9800-7 (1990). The presence of PDI in the transfer protein is supported by evidence showing that (1) the amino terminal 25 amino acids of the bovine 58,000 kDa component of MTP is identical to that of bovine PDI, and (2) disulfide isomerase activity was expressed by bovine MTP following the dissociation of the 58 kDa-88 kDa protein complex. In addition, antibodies raised against bovine PDI, a protein which by itself has no TG transfer activity, were able to immunoprecipitate bovine TG transfer activity from a solution containing purified bovine MTP.
PDI normally plays a role in the folding and assembly of newly synthesized disulfide bonded proteins within the lumen of the endoplasmic reticulum. Bulleid and Freedman, Nature 649-51 (1988). It catalyzes the proper pairing of cysteine residues into disulfide bonds, thus catalyzing the proper folding of disulfide bonded proteins. In addition, PDI has been reported to be identical to the beta subunit of human prolyl 4-hydroxylase. Koivu et al., J. Biol. Chem. 262, 6447-9 (1987). The role of PDI in the bovine transfer protein is not clear. It does appear to be an essential component of the transfer protein as dissociation of PDI from the 88 kDa component of bovine MTP by either low concentrations of a denaturant (guanidine HCl), a chaotropic agent (sodium perchlorate), or a nondenaturing detergent (octyl glucoside) results in a loss of transfer activity. Wetterau et al., Biochemistry 30, 9728-35 (1991). Isolated bovine PDI has no apparent lipid transfer activity, suggesting that either the 88 kDa polypeptide is the transfer protein or that it confers transfer activity to the protein complex.
The tissue and subcellular distribution of MTP activity in rats has been investigated. Wetterau and Zilversmit, Biochem. Biophys. Acta 875, 610-7 (1986). Lipid transfer activity was found in liver and intestine. Little or no transfer activity was found in plasma, brain, heart, or kidney. Within the liver, MTP was a soluble protein located within the lumen of the microsomal fraction. Approximately equal concentrations were found in the smooth and rough microsomes.
Abetalipoproteinemia is an autosomal recessive disease characterized by a virtual absence of plasma lipoproteins which contain apolipoprotein B (apoB). Kane and Havel in The Metabolic Basis of Inherited Disease, Sixth edition, 1139-64 (1989). Plasma TG levels may be as low as a few mg/dL, and they fail to rise after fat ingestion. Plasma cholesterol levels are often only 20-45 mg/dL. These abnormalities are the result of a genetic defect in the assembly and/or secretion of very low density lipoproteins (VLDL) in the liver and chylomicrons in the intestine. The molecular basis for this defect has not been previously determined. In subjects examined, triglyceride, phospholipid, and cholesterol synthesis appear normal. At autopsy, subjects are free of atherosclerosis. Schaefer et al., Clin. Chem. 34, B9-12 (1988). A link between the apoB gene and abetalipoproteinemia has been excluded in several families. Talmud et al., J. Clin. Invest. 82, 1803-6 (1988) and Huang et al., Am. J. Hum. Genet. 46, 1141-8 (1990).
Subjects with abetalipoproteinemia are afflicted with numerous maladies. Kane and Havel, supra. Subjects have fat malabsorption and TG accumulation in their enterocytes and hepatocytes. Due to the absence of TG-rich plasma lipoproteins, there is a defect in the transport of fat-soluble vitamins such as vitamin E. This results in acanthocytosis of erythrocytes, spinocerebellar ataxia with degeneration of the fasciculus cuneatus and gracilis, peripheral neuropathy, degenerative pigmentary retinopathy, and ceroid myopathy. Treatment of abetalipoproteinemic subjects includes dietary restriction of fat intake and dietary supplementation with vitamins A, E and K.
In vitro, MTP catalyzes the transport of lipid molecules between phospholipid membranes. Presumably, it plays a similar role in vivo, and thus plays some role in lipid metabolism. The subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. Wetterau and Zilversmit, Biochem. Biophys. Acta 875, 610-7 (1986). The ability of MTP to catalyze the transport of TG between membranes is consistent with this hypothesis, and suggests that MTP may catalyze the transport of TG from its site of synthesis in the endoplasmic reticulum (ER) membrane to nascent lipoprotein particles within the lumen of the ER.
Olofsson and colleagues have studied lipoprotein assembly in HepG2 cells. Bostrom et al., J. Biol. Chem. 263, 4434-42 (1988). Their results suggest small precursor lipoproteins become larger with time. This would be consistent with the addition or transfer of lipid molecules to nascent lipoproteins as they are assembled. MTP may play a role in this process. In support of this hypothesis, Howell and Palade, J. Cell Biol. 92, 833-45 (1982), isolated nascent lipoproteins from the hepatic Golgi fraction of rat liver. There was a spectrum of sizes of particles present with varying lipid and protein compositions. Particles of high density lipoprotein (HDL) density, yet containing apoB, were found. Higgins and Hutson, J. Lilid Res. 25, 1295-1305 (1984), reported lipoproteins isolated from Golgi were consistently larger than those from the endoplasmic reticulum, again suggesting the assembly of lipoproteins is a progressive event. However, there is no direct evidence in the prior art demonstrating that MTP plays a role in lipid metabolism or the assembly of plasma lipoprotein.
Recent reports (Science, Vol. 258, page 999, 1992; D. Sharp et al, Nature, Vol. 365, page 65, 1993) demonstrate that the defect causing abetalipoproteinemia is in the MTP gene, and as a result, the MTP protein. Individuals with abetalipoproteinemia have no MTP activity, as a result of mutations in the MTP gene, some of which have been characterized. These results indicate that MTP is required for the synthesis of apoB containing lipoproteins, such as VLDL, the precursor to LDL. It therefore follows that inhibitors of MTP would inhibit the synthesis of VLDL and LDL, thereby lowering VLDL levels, LDL levels, cholesterol levels, and triglyceride levels in animals and man.
Canadian Patent Application No. 2,091,102 published Mar. 2, 1994 (corresponding to U.S. application Ser. No. 117,362, filed Sep. 3, 1993 (file DC21b)) which is incorporated herein by reference), reports MTP inhibitors which also block the production of apoB containing lipoproteins in a human hepatic cell line (HepG2 cells). This provides further support for the proposal that an MTP inhibitor would lower apoB containing lipoprotein and lipid levels in vivo. This Canadian patent application discloses a method for identifying the MTP inhibitors 
which has the name 2-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2, 3-dihydro-3-oxo-1H-isoindole hydrochloride and 
which has the name 1-[3-(6-fluoro-1-tetralanyl)-methyl]-4-O-methoxyphenyl piperazine.
EP 0643057A1 published Mar. 15, 1995, discloses MTP inhibitors of the structure 
R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
Y is xe2x80x94(CH2)mxe2x80x94 or 
where m is 2 or 3;
R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (wherein alkyl has at least 2 carbons), diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl (wherein alkyl has at least 2 carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl has at least 2 carbons); all of the aforementioned R1 groups being optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo; or
R1 is a group of the structure 
R11is a bond, alkylene, alkenylene or alkynylene of up to 6 carbon atoms, arylene (for example 
xe2x80x83or mixed arylene-alkylene (for example 
where n is 1 to 6;
R12 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, haloalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy, heteroarylalkyl or cycloalkylalkyl;
Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene of from 1 to 5 carbon atoms;
R13, R14, R15, and R16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, carboxy, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
or R1 is 
wherein p is 1 to 8 and R17 and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R17 and R18 being other than H;
or R1 is 
xe2x80x83wherein
R19 is aryl or heteroaryl;
R20 is aryl or heteroaryl;
R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
R2, R3, R4 are independently hydrogen, halo, alkyl, haloalkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
R5 is alkyl of at least 2 carbons, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, all of the R5 and R6 substituents being optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino (wherein the amino includes 1 or 2 substituents which are alkyl, or aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino; with the proviso that when R5 is CH3, R6 is not H; and where R5 is phenyl, the phenyl preferably includes an ortho hydrophobic substituent such as alkyl, haloalkyl, aryl, aryloxy or arylalkyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl;
R7 is alkyl, aryl or arylalkyl wherein alkyl or the alkyl portion is optionally substituted with oxo; and
including pharmaceutically acceptable salts and anions thereof.
In the formula I compounds, where X is CH2 and R2, R3 and R4 are each H, R1 will be other than 3,3-diphenylpropyl.
In the formula III compounds, where one of R2, R3 and R4 is 6-fluoro, and the others are H, R7 will be other than 4-O-methoxyphenyl.
U.S. application Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e) discloses compounds of the structure 
where 
R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; 
wherein m is 2 or 3;
R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein alkyl has at least 2 carbons, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cyclo-alkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo;
or R1 is a fluorenyl-type group of the structure 
R1 is an indenyl-type group of the structure 
Z1 and Z2 are the same or different and are independently a bond, O, S, 
xe2x80x83with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond; R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylene-alkylene; R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl, with the provisos that
(1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then 
xe2x80x83or a bond and
(2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl;
Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms; R13, R14, R15, and R16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbon-yloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;
R15a and R16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
or R1 is a group of the structure 
wherein p is 1 to 8 and R17 and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R17 and R18 being other than H;
or R1 is a group of the structure 
xe2x80x83wherein
R19 is aryl or heteroaryl;
R20 is aryl or heteroaryl;
R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
R2, R3, R4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkyl-alkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkyl-amino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenyl-aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsul-finyl, arylsulfinylalkyl, arylsulfonyl, alkylsul-fonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 set out above;
R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo 
xe2x80x83are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and 
N-oxides
xe2x80x83thereof; and
pharmaceutically acceptable salts thereof;
with the provisos that where in the first formula X is CH2, and R2, R3 and R4 are each H, then R1 will be other than 3,3-diphenylpropyl, and in the fifth formula, where one of R2, R3 and R4 is 6-fluoro, and the others are H, R7 will be other than 4-(2-methoxyphenyl).
In accordance with the present invention, novel compounds are provided which are inhibitors of MTP and have the structure 
including pharmaceutically acceptable salts thereof, wherein
q is 0, 1 or 2;
A is
(1) a bond;
(2) xe2x80x94Oxe2x80x94; or 
where R5 is H or lower alkyl or R5 together with R2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring.
B is a fluorenyl-type group of the structure: 
xe2x80x83(the above B is also referred to as a fluorenyl-type ring or moiety); or
B is an indenyl-type group of the structure 
Rx is H, alkyl or aryl;
R1 is H, alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)3Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, aryl-alkyl, arylamino, aryloxy, cycloheteroalkyl, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, xe2x80x94PO(R13) (R14), (where R13 and R14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy); R1 can also be aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl or aryloxy)2alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring, such as 1,3-dioxane or 1,3-dioxolane, connected to L1 (or L2 in the case of R2) at the 2-position); 1,3-dioxane or 1,3-dioxolane connected to L1 (or L2 in the case of R2) at the 4-position.
The R1 group may have from one to four substituents, which can be any of the R3 groups or R1 groups, and any of the preferred R1 substituents set out below.
R1 may be substituted with the following preferred substituents: alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may be substituted with alkyl, aryl or heteroaryl), heterocyclylcarbonylamino (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom), alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, 
where
J is: 
xe2x80x83R23, R24 and R25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
R20, R21, R22 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these preferred substituents may either be directly attached to R1, or attached via an alkylene chain at an open position.
R2 is the same or different from R1 and is independently any of the groups set out for R1, H, polyhaloalkyl (such as CF3CH2, CF3CF2CH2 or CF3) or cycloheteroalkyl, and may be substituted with one to four of any of the groups defined for R3, or any of the substituents preferred for R1.
L1 is a linking group containing from 1 to 10 carbons in a linear chain (including alkylene, alkenylene or alkynylene), which may contain, within the linking chain any of the following: one or two alkenes, one or two alkynes, an oxygen, an amino group optionally substituted with alkyl or aryl, an oxo group; and may be substituted with one to five alkyl or halo groups (preferably F).
L2 may be the same or different from L1 and may independently be any of the L1 groups set out above or a singe bond.
R3, R3xe2x80x2, R4 and R4xe2x80x2 may be the same or different and are independently selected from H, halogen, CF3, haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar;
R3a and R3b are the same or different and are independently any of the R3 groups except hydroxy, nitro, amino or thio; 
xe2x80x83are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and including N-oxides.
X (in the fluorenyl type ring) is a bond, or is one of the following groups: 
xe2x80x83wherein
Y is O, Nxe2x80x94R6 or S;
nxe2x80x2 is 0, 1 or 2;
R6 is H, lower alkyl, aryl, xe2x80x94C(O)xe2x80x94R11 or xe2x80x94C(O)xe2x80x94Oxe2x80x94R11; 
R7 and R8 are the same or different and are independently H, alkyl, aryl, halogen, xe2x80x94Oxe2x80x94R12, or
R7 and R8 together can be oxygen to form a ketone;
R9, R10, R9xe2x80x2 and R10xe2x80x2 are the same or different and are independently H, lower alkyl, aryl or xe2x80x94Oxe2x80x94R11;
R9xe2x80x3 and R10xe2x80x3 are the same or different and are independently H, lower alkyl, aryl, halogen or xe2x80x94Oxe2x80x94R11;
R11 is alky or aryl;
R12 is H, alkyl or aryl.
The following provisos apply to formula I compounds:
(a) when R1 is unsubstituted alkyl or unsubstituted arylalkyl, L1 cannot contain amino;
(b) when R1 is alkyl, L1 cannot contain amino and oxo in adjacent positions (to form an amido group);
(c) when R2L2Axe2x80x94 is H2Nxe2x80x94, R1L1 cannot contain amino;
(d) when R1 is cyano, L1 must have more than 2 carbons;
(e) R1L1 must contain at least 3 carbons.
With respect to compounds of the invention IA and IB, R2L2 cannot have an O or N atom directly attached to Sxe2x95x90(O)q or CRx(OH), and for IA, R2L2 cannot be H.
With respect to compounds of the invention I, IA and IB, where R1 or R2 is cycloheteroalkyl, R1 or R2 is exclusive of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo-pyrrolidinyl).
The pharmaceutically acceptable salts of the compounds of formulae I, IA and IB include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof.
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity is provided, wherein a compound of formula I, IA or IB as defined hereinbefore (and including compounds excluded by provisos (a), (b), (c), (d) and (e) set out hereinbefore) is administered in an amount which decreases the activity of microsomal triglyceride transfer protein.
Furthermore, in accordance with the present invention, a method is provided for lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia hypertriglyceridemia and/or hyperglycemia, non-insulin dependent diabetes (Type II diabetes), wherein a compound of formula I, IA or IB as defined hereinbefore (and including compounds excluded by provisos (a), (b), (c), (d) and (e) set out hereinbefore) is administered in an amount which decreases the activity of microsomal triglyceride transfer protein.
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term xe2x80x9cMTPxe2x80x9d refers to a polypeptide or protein complex that (1) if obtained from an organism (e. g., cows, humans, etc.), can be isolated from the microsomal fraction of homogenized tissue; and (2) stimulates the transport of triglycerides, cholesterol esters, or phospholipids from synthetic phospholipid vesicles, membranes or lipoproteins to synthetic vesicles, membranes, or lipoproteins and which is distinct from the cholesterol ester transfer protein [Drayna et al., Nature 327, 632-634 (1987)] which may have similar catalytic properties.
The phrase xe2x80x9cstabilizingxe2x80x9d atherosclerosis as used in the present application refers to slowing down the development of and/or inhibiting the formation of new atherosclerotic lesions.
The phrase xe2x80x9ccausing the regression ofxe2x80x9d atherosclerosis as used in the present application refers to reducing and/or eliminating atherosclerotic lesions.
Unless otherwise indicated, the term xe2x80x9clower alkylxe2x80x9d, xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 12 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents which may be any of the R3 groups, or the R1 substituents set out herein.
Unless otherwise indicated, the term xe2x80x9ccycloalkylxe2x80x9d as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons, forming the ring and which may be fused to 1 aromatic ring as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, 
any of which groups may be optionally substituted with 1 to 4 substituents which may be any of the R3 groups, or the R1 substituents set out herein.
The term xe2x80x9ccycloalkenylxe2x80x9d as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 5 to 20 carbons, preferably 6 to 12 carbons and 1 or 2 double bonds. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexa-dienyl, and cycloheptadienyl, which may be optionally substituted as defined for cycloalkyl.
The term xe2x80x9cpolycycloalkylxe2x80x9d as employed herein alone or as part of another group refers to a bridged multicyclic group containing 5 to 20 carbons and containing 0 to 3 bridges, preferably 6 to 12 carbons and 1 or 2 bridges. Exemplary polycycloalkyl groups include [3.3.0]-bicyclooctanyl, adamantanyl, [2.2.1]-bicycloheptanyl, [2.2.2]-bicyclooctanyl and the like and may be optionally substituted as defined for cycloalkyl.
The term xe2x80x9cpolycycloalkenylxe2x80x9d as employed herein alone or as part of another group refers to a bridged multicyclic group containing 5 to 20 carbons and containing 0 to 3 bridges and containing 1 or 2 double bonds, preferably 6 to 12 carbons and 1 or 2 bridges. Exemplary polycycloalkyl groups include [3.3.0]-bicyclooctenyl, [2.2.1]-bicycloheptenyl, [2.2.2]-bicyclooctenyl and the like and may be optionally substituted as defined for cycloalkyl.
The term xe2x80x9carylxe2x80x9d as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl) and may optionally include one to three additional rings fused to Ar (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloal-koxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, hetero-arylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl or any of the R3 groups, or the R1 substituents set out herein.
The term xe2x80x9caralkylxe2x80x9d, xe2x80x9caryl-alkylnxe2x80x9d or xe2x80x9caryllower alkylxe2x80x9d as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above.
The term xe2x80x9clower alkoxyxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d or xe2x80x9caralkoxyxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
The term xe2x80x9caminoxe2x80x9d as employed herein alone or as part of another group may optionally be substituted with one or two substituents such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and/or cycloalkyl.
The term xe2x80x9clower alkylthioxe2x80x9d, alkylthioxe2x80x9d, xe2x80x9carylthioxe2x80x9d or xe2x80x9caralkylthioxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d, xe2x80x9carylaminoxe2x80x9d, or xe2x80x9carylalkylaminoxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term xe2x80x9cacylxe2x80x9d as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl 
group; examples of acyl groups include alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloal-kanoyl, and the like.
The term xe2x80x9calkanoylxe2x80x9d as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
Unless otherwise indicated, the term xe2x80x9clower alkenylxe2x80x9d or xe2x80x9calkenylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio or any of the R3 groups, or the R1 substituents set out herein.
Unless otherwise indicated, the term xe2x80x9clower alkynylxe2x80x9d or xe2x80x9calkynylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, or any of the R3 groups, or the R1 substituents set out herein.
The term xe2x80x9calkylenexe2x80x9d as employed herein alone or as part of another group refers to alkyl groups as defined above having single bonds for attachment to other groups at two different carbon atoms and may optionally be substituted as defined above for xe2x80x9calkylxe2x80x9d.
Ther terms xe2x80x9calkenylenexe2x80x9d and xe2x80x9calkynylenexe2x80x9d as employed herein alone or as part of another group refer to alkenyl groups as defined above and alkynyl groups as defined above, respectively, having single bonds for attachment at two different carbon atoms.
Suitable alkylene, alkenylene or alkynylene groups or (CH2)m, (CH2)n or (CH2)p (which may include alkylene, alkenylene or alkynylene groups) as defined herein, may optionally include 1, 2, or 3 substituents which include any of the R3 groups, or the R1 substituents set out herein.
Examples of alkylene, alkenylene and alkynylene include 
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.
The term xe2x80x9cmetal ionxe2x80x9d refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
The term xe2x80x9ccycloheteroalkylxe2x80x9d as used herein alone or as part of another group refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), such as 
and the like. The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the R3 groups, or the R1 substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term xe2x80x9cheteroarylxe2x80x9d as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur,and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides, such as 
and the like
Ar may be either aryl or heteroaryl as defined above. 
are the same or different, as defined hereinbefore, and are attached to the central ring of the indenyl or fluorenyl type group at adjacent positions (that is, ortho or 1,2-positions). Examples of such groups include 
wherein u is selected from O, S, and NR7a; R7a is H, lower alkyl, aryl, xe2x80x94C(O)R7b, xe2x80x94C(O)OR7b; R7b is alkyl or aryl.
The heteroaryl groups including the above groups may optionally include 1 to 4 substituents such as any of the R3 groups, or the R1 substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term cycloheteroalkylalkylxe2x80x9d as used herein alone or as part of another group refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH2)p chain.
The term xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheteroaryl-alkenylxe2x80x9d as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a xe2x80x94(CH2)pxe2x80x94 chain, alkylene or alkenylene as defined above.
The term xe2x80x9cpolyhaloalkylxe2x80x9d as used herein refers to an xe2x80x9calkylxe2x80x9d group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.
Preferred are compounds of formula I wherein A is NH,
B is 
X is a bond, oxygen or sulfur; R3 and R4 are independently H or F.
Preferred R1 groups are aryl, preferably phenyl, heteroaryl, preferably imidazoyl, benzimidazolyl, indolyl, or pyridyl (preferably substituted with one of the preferred R1 substituents: arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino), PO(OAlkyl)2, heteroarylthio, benzthiazole-2-thio, imidazole-2-thio, alkyl, or alkenyl, cycloalkyl such as cyclohexyl, or 1,3-dioxan-2-yl.
Preferred R2 groups are alkyl, polyfluoroalkyl (such as 1,1,1-trifluoroethyl), alkenyl, aryl or heteroaryl (preferably substituted with one of the preferred R1 substituents above), or PO(OAlkyl)2.
If R2 is alkyl, 1,1,1-trifluoroethyl, or alkenyl, it is preferred that R1 is other than alkyl or alkenyl.
It is preferred that L1 contains 1 to 5 atoms in the linear chain and L2 is a bond or lower alkylene.
Preferred embodiments of formula IA and formula IB compounds of the invention include those where B, L1, L2, R1 and R2 are as set out with respect to the preferred embodiments of the formula I compounds, q is 0 or 2 and Rx is H.
Also preferred are compounds of the structure 
where B is 
A is NH,
L2 is a bond,
R2 is CF3CH2,,
L1 is xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2CH2xe2x80x94, and
R1 is heteroaryl which is a 5-membered aromatic ring which includes 2 nitrogens, which ring is fused to an aryl ring and is substituted on the aryl moiety. Examples of preferred R1 groups include substituted benzimidazole groups including 
The compounds of formulae I, IA and IB may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.

It will be appreciated that in the above reactions and the reactions to follow, unless otherwise indicated, the moiety xe2x80x9cBxe2x80x9d in the starting materials, intermediates and final products is set out as 
for purposes of illustration only.
It will be appreciated that the xe2x80x9cBxe2x80x9d moiety in the starting materials, intermediates and final products in all reactions set forth herein, unless indicated to the contrary may be any of the fluorenyl-type groups 
as well as any of indenyl-type groups 
The above B moieties (including all fluorenyl-type groups and all indenyl-type groups) are collectively referred to as xe2x80x9cfluorenyl-typexe2x80x9d moieties. The use of the first fluorenyl-type group (as set out in the previous paragraph) in the Reaction Schemes is for purposes of illustration only; any of the 3 fluorenyl groups or 4 indenyl groups as set out above may be employed in any of the Reaction Schemes set out herein in place of 
As indicated above, the starting Compound IV may also be 
The above are collectively referred to xe2x80x9cfluorenyl-type compoundsxe2x80x9d.
As seen in Scheme 1A, in accordance with another aspect of the present invention, the solution of acid II in an inert organic solvent, such as tetrahydrofuran, dioxane or diethyl ether, at a reduced temperature of within the range of from about xe2x88x9240xc2x0 C. to about room temperature, is treated with base such as potassium hydroxide, potassium tert-butoxide, lithium or potassium bis(trimethylsilylamide), or n-butyllithium in an inert organic solvent such as hexane, tetrahydrofuran or diethyl ether, while maintaining temperature of the reaction mixture below from about xe2x88x9240xc2x0 C. to about room temperature. The reaction mixture is treated with R1 halide such as an alkylhalide, for example, 3-phenylpropylbromide to form the alkylated product III.
The above dianion formation reaction is carried out employing a molar ratio of R1halide:acid II of within the range from about 10:1 to about 0.5:1, preferably from about 2:1 to about 0.8:1.
Alternatively, the compound III may be prepared as shown in Scheme 1C(2) wherein fluorenyl-type compound IV is treated with base, such as described above, for example n-butyllithium, and then reacted with R1halide, such as alkylhalide, as described above, to give compound V. Treatment of V with base, such as described hereinbefore such as n-butyl-lithium, followed by treatment of the reaction mixture with CO2 (carboxylation) gives III.
As seen in Scheme 1C(1), acid II may be formed by treating fluorenyl-type compound IV with base (as described above with respect to Scheme 1C(2), followed by treatment with CO2 (carboxylation), to form II.
The amide Ia of the invention is formed by treating III with thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane (optionally-in the presence of dimethylformamide (DMF)) to form the acid chloride IIIA 
Acid chloride IIIA, without separation from the reaction mixture, is treated with amine (R2L2)R5NH at a reduced temperature within the range from about xe2x88x9240xc2x0 C. to about room temperature, to form the amide Ia.
In carrying out the above reaction to form amide Ia, the amine will be employed in a molar ratio to acid chloride IIIA within the range from about 4:1, to about 1:1, optionally in the presence of a tertiary amine base or other acid scavenger.
Alternatively, as seen in Scheme 1B, amide I may be prepared by esterifying III (as shown in Scheme 6) by reacting III with a phenol such as phenol, 4-nitrophenol, or pentafluorophenol and DCC (dicyclo-hexylcarbodiimide) or EDCI (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), optionally in the presence of HOBT (1-hydroxybenzotriazole) through the intermediary of an aryl ester such as phenyl, p-NO2-phenyl or pentafluorophenyl, followed by treatment with a primary or secondary amine to give Ia.
In carrying out the above reaction, the amine will be employed in a molar ratio to ester within the range form about 10:1, to about 1:1.
Alternative formation of amide Ia from acid III and R2R5NH can be carried out via standard literature procedures. 
As seen in Reaction Scheme 2, amides of the invention of structure I can also be prepared by esterifying acid II with an allylic alcohol (as described in Scheme 5), to form ester VI which is treated with base, such as lithium diisopropyl amide or potassium bis(trimethylsilylamide) (optionally in the presence of a triorganosilylchloride, such as trimethylsilylchloride), to give the enolate-Claisen rearrangement acid product VII. Acid VII is then converted to amide Ia of the invention employing conditions as described with respect to Scheme 1.
In carrying out the above reaction, the base treatment and enolate-Claisen rearrangement were performed at a temperature within the range of from about xe2x88x9220 to about 100xc2x0 C., preferably from about 25xc2x0 to about 80xc2x0 C., to form Ia where R1L1 is as defined above in Scheme 2. 
As seen in Reaction Scheme 3, compounds of structure I of the invention can be prepared optionally through amide formation (as described in Reaction Scheme 1 or via other known coupling procedures) from acid II to give compounds of formula VIII. Treatment of VIII with base, such as lithium diisopropylamide or n-BuLi, or potassium bis(trimethylsilyl)amide, followed by quenching the anion with an alkyl halide gives compounds of the formula I. In the specific case where R5 is H, a dianion can be prepared requiringxe2x89xa7two equivalents of base; the dianion can be trapped with an alkyl halide to give I. 
Compounds of the formula I of the invention wherein A=bond can be prepared as shown in Reaction Schemes 4A and 4B.
As seen in Scheme 4A, acid chloride formation under standard methods gives compound IX, which can be reacted with Grignard reagents and copper (I) iodide to give the compound of the invention I.
As seen in Scheme 4B, optionally, ketones can be formed by treatment of X with base, followed by acylation with an acid halide (R2L2COHal), preferably chloride or fluoride, to give compounds of the invention I. 
As seen in Reaction Scheme 5A, compounds of formula I of the invention wherein A=oxygen can be prepared by an acid catalyzed esterification of acid III employing an acid such as H2SO4 or p-toluenesulfonic acid in the presence of an alcohol such as allyl alcohol, ethanol or methanol. Alternatively, activation of the acid III to the acid chloride (with oxaly chloride or thionyl chloride) followed by treatment with an alcohol optionally in the presence of a tertiary amine base or other acid scavenger, gives compounds of formula I.
Various additional methods of activation include mixed anhydride formation ((CF3COO)2 or i-BuOCOC1) or formation of the acylimidazole (carbonyldiimidazole) or with DCC and HOBT in the presence of DMAP (4-dimethylaminopyridine). These activated intermediates readily form esters upon treatment with alcohols.
Scheme 5B involves esterification of acids II to compound XII which is subjected to alkylation to give Ie. 
Compounds of formula Id, with A=bond, can be reduced by methods known in the art, such as sodium borohydride, to give alcohols of the invention IBa (Scheme 5A).
Ketones of formula Id can also be reacted with alkyl metals, such as alkyl lithium or Grignard reagents, to give the tertiary alcohols of the invention of structure IBb (Scheme 6B). 
Compounds of formula I where A is xe2x80x94NHxe2x80x94 (amides) can be prepared by the methods shown in Reaction Scheme 7A from known compound IV. Treatment of compound IV with base, such as n-BuLi, followed by reacting the anion with an isocyanate gives compound XIII. Compound XIII can be further transformed to compounds of the formula If as shown above.
In a similar manner, as seen in Scheme 7B, compound V can be transformed to compounds of the formula If. 
where PG is an oxygen protecting group, such as t-Bu(CH3)2Si or tBu(Ph)2Sixe2x80x94 
Compounds I of the invention may be modified by the various transformations set out in Reaction Scheme 8. Protected alcohol XIVa can be converted into a wide variety of functional groups through the intermediacy of a halide Ih. For example, the alcohol Iq can be converted to the halide Ih of the invention by either activation through the sulfonate ester (tosyl chloride, or mesyl chloride) and iodide displacement (NaI or KI in acetone or 2-butanone), or by reaction with triphenylphosphine, I2 and imidazole. The iodide Ih can undergo an Arbuzov reaction to form phosphonates, phosphinates and phosphine oxides of the invention Im. The Arbuzov reaction can be accomplished with phosphites, phosphinites, and phosphonites (for example, R13R14POalkyl or R13R14POSi(alkyl)3 or R13R14POH, the latter being in the presence of a base such as butyllithium, sodium hydride or sodium bis(trimethylsilylamide)) at temperatures within the range from about xe2x88x9220xc2x0 C. to about 180xc2x0 C. Alternately, displacement reactions to form amines Il, thioethers In or nitriles Io can be easily accomplished. To form amines Il, iodide Ih, can be treated with amines in DMF with or without K2CO3. Thioethers In can also be formed under similar conditions. The nitrites If are prepared from either KCN or NaCN in hot DMSO. The alcohol can also be oxidized to a carboxylic acid. The acids can also be used as intermediates to form amides of the invention Ik by methods previously described. The sulfur atom of In can be oxidized under standard conditions to sulfoxide Ip or sulfone Iq. 
Acetals of the invention Is can be prepared from alcohol Ig by oxidation of the alcohol to the aldehyde XV. Prefered reagents to accomplish the transformation are either the Swern oxidation ((COCl)2, DMSO, triethylamine) or Dess-Martin Periodinane. The aldehyde XV can be converted to the acetal Is with excess alcohol such as 1,3-propanediol or ethylene glycol in the presence of a catalytic amount of acid such as H2SO4 or p-toluenesulfonic acid, optionally in the presence of a dehydrating agent such as 4A sieves or trimethyl orthoformate. 
An addition procedure to incorporate the phosphonate in the N-alkyl chain is shown in Scheme 11. Carboxylic acid II is converted to the amide of the invention It as follows. Activation of the acid II to the acid chloride (with oxalyl chloride or thionyl chloride) followed by treatment with an aminoalcohol such as 1,5-aminopentanol or 1,3-aminopropanol gives amide of the invention It. Various additional methods of activation include mixed anhydride formation ((CF3COO)2 or i-BuOCOCl) or formation of the acylimidazole (carbonyldiimidazole) or with DCC and HOBT in the presence of DMAP. These activated intermediates readily form amides upon treatment with aminoalcohols. The alcohol It can then be converted to the iodide Iu by either activation through the sulfonate ester (tosyl chloride or mesyl chloride) and iodide displacement (NaI or KI in acetone or 2-butanone) or by reaction with triphenylphosphine, I2 and imidazole. The iodide Iu can be reacted with a phosphorus (III) derivative R13R14P(OQ1), for example triethylphosphite, tributylphosphite or (phenyl)2POC2H5, in an Arbuzov reaction to give the phosphonate of the invention Iv. 
Reaction Scheme 12 outlines the general procedure for the preparation of the sulfides, sulfones and sulfoxides IA of the invention. Ketone XVI can be reduced with NaBH4 to give alcohol XVII. The alcohol XVII can undergo solvolysis by treatment with acid (H2SO4, or BF3-etherate, TiCl4) in the presence of a thiol (R2L2SH) such as butanethiol to give thio compound of the invention IAa. An alternate method to give IAa proceeds via acetate formation (AC2O), followed by the solvolysis reaction. Thioether IAa can be alkylated (n-BuLi, R1L1Hal) by treatment with base and trapping with an alkyl halide to give sulfide of the invention IAb. The thioether in IAb can be oxidized to the sulfoxide IAc by mCPBA (m-chloroperbenzoic acid), or NaIO4. Sulfone IAd can be obtained from IAb by oxidation with, for example, mCPBA by employing 2 or more equivalents of oxidizing agent.
Alternately, ketone XVI can be reacted with a Grignard to give XVII which can undergo solvolyis reactions (H2SO4, R2L2SH, or BF3-etherate, R2SH) to give sulfide IAb. The sulfones and sulfoxides can be obtained as described above. 
Compounds of the invention of formula I where A is 
and R5 is preferably H, and L1 is a linking group as defined above can be prepared as shown in Reaction Scheme 13.
As seen in Scheme 13, acid II is treated with base and alkylated by reaction with halide XX, as described with respect to Scheme 1, to form alkylated intermediate IIIA. IIIA is reacted with amine XXI (using the amide formation procedure as described in Scheme 1) to form amide of the invention ID.
Where M in ID is NO2, NHCORq or NHSO2Rs, ID represents a final product.
Where M includes a protecting group, the protecting group may be removed as shown in Scheme 18.
Where desired, acid II may undergo amide formation by reaction with amine XXI to form amide XXII via various known procedures, which is then alkylated to form ID. 
Compounds of the invention of formula I, IA or IB where R1 is aryl or heteroaryl may be prepared as shown in Reaction Schemes 14(A) and 14(B).
In Scheme 14(A) compounds of formula Ixe2x80x2, IAxe2x80x2 or IBxe2x80x2 (where R1 is aryl or heteroaryl) may be prepared by coupling compound XXIII with compound Il, IA1 or IB1, respectively, optionally in the presence of a base as described with respect to Scheme 1.
Compounds Ixe2x80x2, IAxe2x80x2, IBxe2x80x2, Ixe2x80x3, IIAxe2x80x3 and IBxe2x80x3 may be subjected to deprotection and/or further converted, where necessary as shown in Scheme 18.
In Scheme 14(B) compounds of formula Ixe2x80x3, IAxe2x80x3 or IBxe2x80x3 (where R1 is heteroaryl and {circle around (Ar)} is linked to L1 via a ring nitrogen)) may be prepared by coupling XXIV with I1, IA1 or IB1, optionally in the presence of a base. 
Compounds of the invention of formula I, IA or IB where R1 is {circle around (Ar)} may be prepared as shown in Reaction Scheme 15.
In Scheme 15, acetylenic starting compound I2, IA2 or IB2 is made to undergo a Castro-Stevens cross coupling with XXV in the presence of a catalyst, such as palladium, Pd(Ph3P)4 or Pd(Ph3P)2Cl2 in the presence of an amine (e.g. BuNH2, Et3N) and a Copper (I) salt (e.g. CuI) to form compound of the invention I3, IA3 or IB3, respectively, and subjecting I3, IA3 or IB3 to hydrogenation to form compound of the invention I4, IA4 or IB4.
Compound I3,IA3, IB3, I4, IA4 or IB4 may be subjected to deprotection and further conversion if necessary, as described in Reaction Scheme 18. 
In an alternative procedure as shown in Reaction Scheme 16 compound I4, IA4 or IB4 may be prepared starting with compound I5, IA5 or IB5, respectively, which is made to undergo a cross coupling reaction with XXV in the presence of a palladium or nickel catalyst, to form I6, IA6 or IB6, respectively, which is hydrogenated to form I4, IA4 or IB4, respectively. 
Compounds of the invention of formula I, IA or IB where L1 is an N-containing moiety may be prepared as shown in Reaction Scheme 17 wherein starting compound I7, IA7 or IB7 is made to undergo oxidative cleavage, as described above, to form aldehyde I8, IA8 or IB8, respectively, which is subjected to reductive amination by reaction with amine XXVI, as described above, to form compound of the invention I9, IA9 or IB9, respectively.
Compound I9, Ia9 or IB9 may undergo deprotection, if necessary, as shown in Scheme 18. 
In a preferred method, superior yields of final products (I11, IA11, IB11, I12, IA12, IB12) are obtained when the intermediate I13, IA13, IB13 is reacted with RqCOCl, RnNxe2x95x90Cxe2x95x90O or RsSO2Cl immediately after formation of I13, IA13 or IB13, preferably in situ.
1) xcexa9 represents 
2) {circle around (Ar)} is aryl or heteroaryl
3) M is NO2, Nxe2x80x94PG, NHCORq, NHSO2Rs, N(PG2)CORq, N(PG2)SO2Rs Examples of protecting groups for nitrogen (PG1) are Stabase (xe2x80x94Si(CH3)2xe2x80x94CH2CH2xe2x80x94(CH3)2Sixe2x80x94), BOC (t-ButylOxe2x80x94COxe2x80x94) and bis-BOC.
4) Examples of PG2 or BOC, CH3)3Sixe2x80x94 or t-Bu(CH3)2Sixe2x80x94
5) Deprotection according to the prior art.
The compounds of the invention may be employed in preventing, stabilizing or causing regression of atherosclerosis in a mammalian species by administering a therapeutically effective amount of a compound to decrease the activity of MTP.
The compounds of the invention can be tested for MTP inhibitory activity employing the procedures set out in U.S. application Ser. No. 117,362 filed Sep. 3, 1993, employing MTP isolated from one of the following sources:
(1) bovine liver microsomes,
(2) HepG2 cells (human hepatoma cells) or
(3) recombinant human MTP expressed in baculovirus.
The compounds of the invention may also be employed in lowering serum lipid levels, such as cholesterol or triglyceride (TG) levels, in a mammalian species, by administering a therapeutically effective amount of a compound to decrease the activity of MTP.
The compounds of the invention may be employed in the treatment of various other conditions or diseases using agents which decrease activity of MTP. For example, compounds of the invention decrease the amount or activity of MTP and therefore decrease serum cholesterol and TG levels, and TG, fatty acid and cholesterol absorption and thus are useful in treating hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, pancreatitis, hyperglycemia and obesity.
The compounds of the present invention are agents that decrease the activity of MTP and can be administered to various mammalian species, such as monkeys, dogs, cats, rats, humans, etc., in need of such treatment. These agents can be administered systemically, such as orally or parenterally.
The agents that decrease the activity or amount of MTP can be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable formulation. The above dosage forms will also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms are quite satisfactory as well.
The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result. In general, the dosage forms described above may be administered in amounts of from about 5 to about 500 mg per day in single or divided doses of one to four times daily.